Transcript Slide 1

POLYMORPHISMS OF SELECTED CHEMOKINE AND CYTOKINE GENES AND
RISK FOR FAILURE IN TOTAL HIP ARTHROPLASTY
Z. Navratilova1, J. Gallo2, F. Mrazek1, R. Fillerova1, M. Petrek1
1 Laboratory
of Immunogenomics and Proteomics, Dept. of Immunology
2 Dept. of Orthopaedics
Palacky University and University Hospital Olomouc, Czech Republic
Background
Methods
Periprosthetic osteolysis
Periprosthetic osteolysis (OL) is major complication
of the total hip athroplasty (THA) which can result in
aseptic loosening and revision surgery.
1. Subjects
205 unrelated Czech patients with cementless type THA - stratified according to:
1) THA failure (reoperation) and 2) severity of OL. Table 1.
Tab 1. Characteristics of the patients with THA stratified according to the need for reoperation and OL severity
Revised THA
Functional primary THA
Mild OL (Types I, II)
Severe OL (Types III-IV)
157
48
89
116
Gender (men/women)
49/108
19/29
35/54
33/83
Age at index surgery
46 (24-68)
48 (32-58)
48 (27-58)
45 (24-68)
Osteoarthritis
22
26
35
13
Dysplastic hip
76
9
23
62
Other diagnosis
59
13
31
41
Patients, N
OL is considered as complex inflammatory
response to wear particles liberated from the
prosthetic surfaces.
Primary diagnosis
Recent findings support concept of genetic
component of OL and aseptic loosening.
Severe and mild OL according to Saleh et al. classification (J Bone Joint Surg Am, 83: 1040, 2001).
Selection of candidate genes
Cytokines and chemokines are though to be plausible
candidates for implication in the pathogenesis of OL
and aseptic loosening.
Here we selected genes encoding six molecules
involved in two (cytokine and chemokine) signalling
pathways:
1) IL-17A, IL-17F and IL-23R are important regulators
of immune response and may be associated with bone
turnover
2) CXCL1, CXCL5 and their receptor CXCR2 promote
accumulation of immune cells (namely neutrophils) in
site of inflammation
2. Genotyping
Genotyping technique:
Polymerase Chain Reaction with Sequence Specific Primers (PCR-SSP). Table 2.
Tab 2. Investigated SNPs and their alleles
Chemokines
Cytokines
Gene
Rs numbers
Genetic variants
Gene
Rs numbers
Genetic variants
CXCL1
Rs4074
G/A
IL-17A
Rs2275913
G/A
CXCL5
Rs425535
G/A
IL-17F
Rs763780
T/C
CXCR2
Rs2230054
C/T
IL-23R
Rs7517847
T/G
3. Statistics
Conformity of the distribution of genotypes to the Hardy-Weinberg equilibrium: χ2 goodness-of-fit test
Differences between allelic, genotype and phenotype („carriage rate“) frequencies: χ2 test.
Hypothesis and objective
Results
Genotypes of all six investigated SNPs were distributed in compliance with the Hardy-Weinberg equilibrium.
The distribution of alleles among the patients with THA corresponded to the frequencies observed in Czech
healthy control population and other Caucasians (Figure 1).
Wear Particles
Inflammation
Genetic Factors
Out of investigated variants, CXCL1 rs4074 AA genotype was more frequent in the patients with functional
primary prosthesis compared to those with revised THA (p = 0.02, Figure 2). The frequency of AA genotype in
whole group of the patients with THA was same as that in Czech population (0.12). No further difference in the
distribution of tested SNPs was observed between revised and unrevised THA patients (p > 0.05, Figure 3).
Bone Turnover
None of the explored cytokine / chemokine SNPs was associated with the severity of OL (p > 0.05).
Periprosthetic Osteolysis
Fig 1. The frequency of less common alleles for six investigated
SNPs in the patients with THA compared to control Czech population.
Premature THA Failure
Fig 2. Proportion of CXCL1 rs4074 AA genotype in the patients with
total hip athroplasty (THA) failure compared to those in the patients
with functional primary THA
0.30
0.47 0.48
0.5
0.4
0.25
0.40
0.35 0.36
0.41
0.37
0.35
0.3
0.2
0.11
0.1
0.09
0.03
0.06
rare AA genotype frequency
The aim of the present study was to investigate
possible association of single nucleotide
polymorphisms (SNPs) within the genes encoding
for CXCL1, CXCL5, CXCR2, IL-17A, IL-17F and
IL-23R with severity of OL and THA failure
(revision).
rare alleles frequencies
0.6
0.21
0.20
0.15
0.09
0.10
0.05
0
CXCL1
rs4074
CXCL5
rs425535
CXCR2
rs2230054
IL-17A
rs2275913
IL-17F
rs763780
IL-23R
rs7517847
0.00
THA failure
the patients with THA versus
control Czech population
p > 0.05 (for all SNPs)
Conclusions
functional primary THA
THA failure versus functional primary THA p = 0.02
Fig 3. The frequencies of less common alleles for six investigated
SNPs in the patients with revised THA compared to those with
functional primary THA.
0.60
Our preliminary findings should be replicated in larger THA cohorts, optimally including more detailed
and functional analysis of the CXCL1 gene variability. Studies of CXCL1 role in OL and aseptic
loosening of THA are desirable as well.
Conclusions
rare alleles frequencies
In this pilot study, less common AA genotype of CXCL1 rs4074 SNP appeared as a marker associated
with the protection from total hip arthroplasty failure (revision).
0.50
0.46
0.49
0.41
0.44
0.40
0.38
0.40
0.43
0.33
0.30
0.20
0.11 0.11
0.10
0.04
0.02
0.00
CXCL1
rs4074
revised THA
CXCL5
rs425535
CXCR2
rs2230054
versus
IL-17F
rs763780
IL-23R
rs7517847
functional primary THA:
p > 0.05
Grant support: GACR 310/09/P377, IGA NS 10260 and MSM6198959223.
IL-17A
rs2275913